The iontophoretic transdermal delivery of pharmaceutical compounds relates to introducing ions of soluble salts of therapeutic agents into tissues of the body under the influence of an applied electric field. Recent reviews have summarized the features and benefits of iontophoretic transdermal delivery systems as compared with passive transdermal systems as well as with other means of delivering drugs into the bloodstream, for example, O. Wong, "Iontophoresis: Fundamentals", in Drugs Pharm. Sci. (1994), 62 (Drug Permeation Enhancement), 219-46 (1994); and P. Singh et al., "Iontophoresis in Drug Delivery: Basic Principles and Applications", Critical Reviews in Therapeutic Drug Carrier Systems, 11(2&3):161-213 (1994). Thus, it is known that in certain cases when oral delivery of a particular drug may be ineffective or unacceptable because of poor GI absorption, extensive first pass effect or other side effects, transdermal delivery may provide an advantageous method of delivering such drugs. However, while topical delivery using passive transdermal delivery devices may provide an acceptable alternative in many cases, there are still certain circumstances when an adequate dose of the drug cannot be practically delivered due to inadequate migration rates, rather long lag times, cannot be practically delivered due to inadequate migration rates, rather long lag times, inter- and intra-patient flux variability, the need for unacceptably large transdermal patches and/or concentration levels of the drug that cause skin irritation effects. In some cases, an iontophoretic transdermal delivery system may be useful to overcome these types of difficulties.
Passive transdermal delivery has been reported of phosphate compounds, and in particular bisphosphonates, which are derivatives of methanediphosphoric acid, in U.S. Pat. No. 5,133,972 and iontophoretic delivery of etidronate, which is also a bisphosphonate drug, has been reported in Kasting and Keister (J. Membrane Sci., 35, 137-159, 1988). These transdermal bisphosphonate delivery systems are intended to provide drug delivery methods which avoid or reduce the problems associated with oral delivery of bisphosphonate compounds. These compounds which are known to be useful for the treatment of Paget's disease, osteoporosis and bone metasteses.
However, in passive transdermal delivery systems, the flux of the drug across skin is low and highly scattered because of the polarity of the delivered form of the drug over the range of pH values from 2 to 10. Since an iontophoretic delivery system uses an external electrical power source to control the transport of the drug across skin, the drug flux can be increased while simultaneously reducing the variability in its delivery. However, it has now been found that in the transdermal delivery of bisphosphonates, an unusual pattern of skin irritation is observed for in vivo studies in both passive and iontophoretic delivery systems. In particular, as distinct from the skin irritation that may be produced due to extremes in pH that occur in iontophoretic systems, for which preventive measures have been disclosed, such as in U.S. Pat. Nos. 4,915,685 or 5,224,927, a delayed onset of skin irritation, from a few days to a week, is typically observed after the transdermal bisphosphonate delivery system is removed from the skin to which it was attached. The level of irritation depends on the concentration of the, drug and, for the case of iontophoresis, also on the applied current. In addition to moderate to severe erythema and/or edema, white precipitates may also be observed. In mild cases, the skin may resolve after a period of time, typically 3 to 4 weeks. In severe cases, necrosis may form.